Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma

Dirk Bausch, Thomas Pausch, Tobias Krauss, Ulrich Theodor Hopt, Carlos Fernandez-Del-Castillo, Andrew L. Warshaw, Sarah P Thayer, Tobias Keck

Research output: Contribution to journalArticle

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Abstract

Background: Vascular endothelial growth factor (VEGF) that is secreted by tumor cells plays a key role in angiogenesis. Matrix metalloproteinase 9 (MMP-9) is produced by inflammatory cells, such as stromal granulocytes (PMN), remodels the extracellular matrix and is known to promote angiogenesis indirectly by interacting with VEGF. The aim of this study was to determine the role of PMN-derived MMP-9, its interaction with VEGF, and the efficacy of anti-angiogenic therapy targeting MMP-9 with oral Doxycycline and VEGF with Bevacizumab in pancreatic cancer (PDAC). Methodology/principal findings: Inhibitors to MMP-9 (Doxycycline) and VEGF (Bevacizumab) were used alone or in combination in an in vitro angiogenesis assay to test their effect on angiogenesis caused by MMP-9, VEGF, PMN and PDAC cells. In an in vivo model of xenografted PDAC, treatment effects after 14 days under monotherapy with oral Doxycycline or Bevacizumab and a combination of both were evaluated. In vitro, PMN-derived MMP-9 had a direct and strong proangiogenic effect that was independent and additive to PDAC-derived VEGF. Complete inhibition of angiogenesis required the inhibition of VEGF and MMP-9. In vivo, co-localization of MMP-9, PMN and vasculature was observed. MMP inhibition with oral Doxycycline alone resulted in a significant decrease in PDAC growth and mean vascular density comparable to VEGF inhibition alone. Conclusions/significance: PMN derived MMP-9 acts as a potent, direct and VEGF independent angiogenic factor in the context of PDAC. MMP-9 inhibition is as effective as VEGF inhibition. Targeting MMP-9 in addition to VEGF is therefore likely to be important for successful anti-angiogenic treatment in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)235-243
Number of pages9
JournalAngiogenesis
Volume14
Issue number3
DOIs
StatePublished - Sep 1 2011

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Matrix Metalloproteinase 9
Granulocytes
Vascular Endothelial Growth Factor A
Adenocarcinoma
Neutrophils
Switches
Doxycycline
Pancreatic Neoplasms
Angiogenesis Inducing Agents
Matrix Metalloproteinases
Extracellular Matrix
Blood Vessels
Tumors
Assays
Cells

Keywords

  • MMP-9
  • Neutrophil granulocyte
  • Pancreatic cancer
  • VEGF

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Cite this

Bausch, D., Pausch, T., Krauss, T., Hopt, U. T., Fernandez-Del-Castillo, C., Warshaw, A. L., ... Keck, T. (2011). Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma. Angiogenesis, 14(3), 235-243. https://doi.org/10.1007/s10456-011-9207-3

Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma. / Bausch, Dirk; Pausch, Thomas; Krauss, Tobias; Hopt, Ulrich Theodor; Fernandez-Del-Castillo, Carlos; Warshaw, Andrew L.; Thayer, Sarah P; Keck, Tobias.

In: Angiogenesis, Vol. 14, No. 3, 01.09.2011, p. 235-243.

Research output: Contribution to journalArticle

Bausch, Dirk ; Pausch, Thomas ; Krauss, Tobias ; Hopt, Ulrich Theodor ; Fernandez-Del-Castillo, Carlos ; Warshaw, Andrew L. ; Thayer, Sarah P ; Keck, Tobias. / Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma. In: Angiogenesis. 2011 ; Vol. 14, No. 3. pp. 235-243.
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AU - Hopt, Ulrich Theodor

AU - Fernandez-Del-Castillo, Carlos

AU - Warshaw, Andrew L.

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AB - Background: Vascular endothelial growth factor (VEGF) that is secreted by tumor cells plays a key role in angiogenesis. Matrix metalloproteinase 9 (MMP-9) is produced by inflammatory cells, such as stromal granulocytes (PMN), remodels the extracellular matrix and is known to promote angiogenesis indirectly by interacting with VEGF. The aim of this study was to determine the role of PMN-derived MMP-9, its interaction with VEGF, and the efficacy of anti-angiogenic therapy targeting MMP-9 with oral Doxycycline and VEGF with Bevacizumab in pancreatic cancer (PDAC). Methodology/principal findings: Inhibitors to MMP-9 (Doxycycline) and VEGF (Bevacizumab) were used alone or in combination in an in vitro angiogenesis assay to test their effect on angiogenesis caused by MMP-9, VEGF, PMN and PDAC cells. In an in vivo model of xenografted PDAC, treatment effects after 14 days under monotherapy with oral Doxycycline or Bevacizumab and a combination of both were evaluated. In vitro, PMN-derived MMP-9 had a direct and strong proangiogenic effect that was independent and additive to PDAC-derived VEGF. Complete inhibition of angiogenesis required the inhibition of VEGF and MMP-9. In vivo, co-localization of MMP-9, PMN and vasculature was observed. MMP inhibition with oral Doxycycline alone resulted in a significant decrease in PDAC growth and mean vascular density comparable to VEGF inhibition alone. Conclusions/significance: PMN derived MMP-9 acts as a potent, direct and VEGF independent angiogenic factor in the context of PDAC. MMP-9 inhibition is as effective as VEGF inhibition. Targeting MMP-9 in addition to VEGF is therefore likely to be important for successful anti-angiogenic treatment in pancreatic cancer.

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